Protein neurotransmitters are involved in initiating and maintaining complex behaviors in mammals. Furthermore, abnormalities of protein neurotransmission will undoubtedly be found to underlie some neuropsychiatric illness. The development of models to study abnormal protein neurotransmission and the correlation of these models with clinical disease, however, has been impeded by the lack of clinically or experimentally useful drugs to modify protein neurotransmission and by the lack of clinical methods to evaluate protein neurotransmission in the behaviorally disturbed. The purpose of this proposal is two-fold: First, basic investigations into posttranslational processing of peptide neurotransmitters in the central nervous system; and second, a search for evidence of abnormal protein neurotransmission in the behaviorally and cognitively disabled. The first project will include basic, biochemical studies of peptide amidation, N-terminal glutaminyl cyclization, and the posttranslational processing of the presursor for TRH. This project is concerned with isolation, purification, definition of the catalytic mechanisms, immunocytochemical localization and the physiological regulation of the enzymes catalyzing these posttranslational modifications. The third aspect of this project, studies of the posttranslational processing of TRH precursor, is intended to serve as a model for studies of those special neuronal adaptations required to maintain adequate stores of protein neurotransmission in distal nerve terminals. The second major program will determine whether a constitutional deficiency or abnormality in posttranslational processing may be associated with mental retardation, affective disorder or psychosis in young and old adults who are either severely mentally disabled or psychiatrically ill. Serum levels of peptidyl glycine monooxygenase and glutamine cyclotransferase will be determined in these types of patients and correlated with their clinical illness. Methods involved in this research will include high pressure liquid chromatography, radioimmunoassay, generation of antisera, amino acid analysis, mass spectroscopy, immunoaffinity chromatography, gel chromatography, fast protein liquid chromatography, isoelectric focusing, thin layer chromatography, and solid phase and liquid protein synthetic chemistry.